All publications cited herein are incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Worldwide, an estimated 350,000 people are diagnosed with leukemia each year, with approximately 257,000 deaths annually (International Agency for Research on Cancer). In the U.S. alone, an estimated 274, 930 people are living with leukemia, with about 90 percent of all leukemia diagnosed in adults (World Health Organization). In 2012, 47, 150 new patients were diagnosed, with only about 50 percent expected to survive (American Cancer Society). While conventional frontline therapies are effective in many cases, it is obvious from the low survival rate of leukemia patients that there is an imperative for improvement.
Leukemia is very expensive to treat, and many patients are unable to afford treatment. Most patients with leukemia are treated with chemotherapy (Ohio State University's Comprehensive Cancer Center). Just one chemotherapy treatment can cost $150,000, usually with several treatments needed. An optional treatment, bone-marrow transplants are known to cost $250,000 or more (Edgar Law Firm, Santa Rosa, Calif.). The National Cancer Institute's Cancer Trends Progress Report: 2011-2012 update estimates that $5.4 billion is spent in the United States each year on leukemia treatment, or more than $114,500 for each of the 47, 150 patients diagnosed in 2012.
Ewing sarcoma family of tumors (EFT) is an aggressive disease that occurs exclusively in humans and disproportionally affects adolescents and young adults. EFT is the second most common malignant bone tumor that can also arise in extra skeletal soft tissues. This group of undifferentiated tumors is an orphan cancer; the parental lineage of which is unknown. Phenotypically it appears as a primitive stem-cell like tumor with round blue cells and increased mitotic activity. Gene profiling studies detect increased expression for biomarkers from both the neural and mesenchymal lineages. Clinically, it is a highly invasive disease with approximately 20-25% of the patients having metastatic disease at diagnosis. Those lacking overt spread of disease likely harbor micro-metastases as is evident by the high relapse rate at distant sites following surgical resection. The outcomes in patients with metastatic disease is dismal with long term outcome ranges from 20%-40% despite intensive multi-modal therapy.
Unlike osteosarcoma, the most common malignant bone tumor, and various other adult cancers, EFT is associated with a paucity of genomic mutations in genes driving crucial signal transduction pathways. EFT pathogenesis is significantly dependent on the genomic networks that are either repressed or triggered into action by the genetic aberration, EWS/ETS fusion gene that is constitutively active in the tumor cells. The fusion of the EWS gene on chromosome 22q24 with one of five E-twenty-six (ETS) transcription factor gene family members (FLI1, ERG, ETV1, E1AF, and FEV) occurs as a result of chromosomal translocations in this family of tumors.
Decreasing post-transcriptional fusion-gene levels by using RNAi technology significantly impairs the proliferative, invasive, and tumorigenic phenotype of Ewing sarcoma both in vitro and in vivo. Thus oncogenic activity of the EWS/ETS fusion genes makes them ideal therapeutic targets and such fusion-related targeted therapy is currently being clinically evaluated. However this may prove challenging as fusion proteins are known to be difficult targets due to their disordered protein nature and lack of intrinsic enzymatic activity. Other approaches to tackle the disease are also currently being investigated. These are either therapeutic agents that can potentially reverse EWS/FLI-driven signatures or oncogene-targeted drug therapy that impair significant cancer-related signaling pathways that are necessary for tumor existence. Single drug therapies have failed in trials despite having strong biological data to support them. To date no standard therapy exists for second-line treatment of relapsed and refractory Ewing sarcoma, despite extensive protocol-driven clinical research evaluating dose intensification and schedule optimization.
With incorporation of high-throughput genomics and the current knowledge of the transcribed genome, our search for molecular characterization of the tumor led us to identify a long non-coding RNA (lncRNA), FEZF1-AS1 that is strongly associated with EFT. FEZF1-AS1 is regulated by EWS-FLI1 in EFT and its expression is required for neural features of this tumor. Like EFT, a developmental tumor occurring only in humans, FEZF1-AS1 is expressed only in humans during the development of the nervous system. It imparts invasive potential to the tumor and thus helps maintain the aggressiveness of this disease. Given the role of FEZF1-AS1 in EFT, it can be a therapeutic target to treat this invasive disease.
Herein, we provide a drug delivery system, in which hybrid polymerized liposomal nanoparticles (HPLNs) are utilized to encapsulate cancer drugs (for example, therapeutic agents that target FEZF1-AS1) and deliver the cancer drugs to the cancer cells. The described delivery system can be used for encapsulating virtually any drug of interest and targeting to any tissue for which there is a known unique or specific cell marker. Therefore this invention provides a very versatile platform technology.
The HPLNs described herein offer a major advantage over many other types of delivery particle substances by employing a unique type of nanoparticle material that is both biocompatible and enhances the bioavailability of the drugs encapsulated within. In addition, the technology is customized by adjusting the particle properties so that a high amount of the drug agent is contained within, and actually solidified into a crystal. Still another differentiating feature is a customization process that appends a tumor-targeting molecule to the surface of the particle, thus improving the particles' selectivity in accessing tumorous cells while avoiding healthy tissues.
Through the use of drugs encapsulated in HPLNs, physicians treating cancer patients may see a significant increase in the therapeutic window of existing cancer chemotherapeutic substances by minimizing dose-related toxicity on non-cancerous cells. For these patients, the HPLNs described herein hold the promise of more effective treatment, accomplished through several significant attributes: a) shorter treatment time, b) fewer hospital visits, c) less damage to normal tissues, d) more rapid recovery, and e) greater chance of survival.